CN110596230A - MALDI-TOF-MS-based high-throughput analysis method for capsule single-particle medicine - Google Patents
MALDI-TOF-MS-based high-throughput analysis method for capsule single-particle medicine Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
- G01N27/64—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode using wave or particle radiation to ionise a gas, e.g. in an ionisation chamber
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
Abstract
The invention discloses a MALDI-TOF-MS-based high-throughput analysis method for capsule single-particle medicines, which comprises the following steps: spotting the drug main component standard solution on a target plate, drying, performing matrix spotting, and performing MALDI-TOF-MS analysis and detection; adhering the drug particles in the capsule to be detected on a target plate through a conductive double-sided adhesive, and directly performing MALDI-TOF-MS analysis and detection; and identifying the authenticity of the capsule to be detected by comparing the MALDI-TOF-MS graphs of the medicine particles of the capsule to be detected and the medicine main component standard substance. When the MALDI-TOF-MS method is adopted to detect the single-particle drugs, the matrix and the pretreatment are not needed, and the detection can be directly carried out, so that the use of an organic solvent is avoided to the greatest extent, and the analysis and detection time is greatly shortened because the complex pretreatment process is not needed.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to a MALDI-TOF-MS-based high-throughput analysis method for capsule single-particle drugs.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The control of the quality of the medicine is very important for the health and life safety of people, and is one of the important problems concerning the national civilization. However, the safety problems of the medicines are frequent nowadays, and the medication safety of people is seriously threatened by adulteration of the medicines and even counterfeit medicines. In order to effectively reduce and timely prevent the occurrence of the safety problem of the medicine, it is necessary to develop an analysis technology and a research method which can rapidly and sensitively detect various active medicine main components.
The capsule medicine is one of the clinically used dosage forms, and its contents are usually powders or granules which are irritating to the esophagus and gastric mucosa, or medicines which are bad in taste, easily volatilized, easily decomposed by saliva in the oral cavity, and easily inhaled into the trachea. At present, no special detection method exists for the medicine with the dosage form, and the general steps are that the content of the capsule medicine is taken out and dissolved, and the content is further analyzed by using the conventional chromatographic techniques (gas chromatography, liquid chromatography, capillary electrophoresis, ion chromatography and the like) and the chromatographic-mass spectrometry combined technology (gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry) and the like. The conventional analysis methods have complex pretreatment steps, time and labor are wasted in the detection process, the reagent consumption is high, the reagent toxicity is high, and the method is not environment-friendly. Therefore, there is an urgent need to develop a simple, rapid, green and efficient analysis method for successfully identifying or quantitatively screening the main drug components in the capsule drug.
Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) is a novel soft ionization mass spectrometry developed in recent years, and the MALDI-TOF-MS has the characteristics of high sensitivity, high accuracy, high resolution and the like, and the soft ionization mode can well ensure the integrity of molecules, so that the MALDI-TOF-MS not only becomes a powerful tool for analyzing biomacromolecules, but also shows great advantages and potentials in the structural identification and analysis of small molecular compounds. The inventors found that MALDI-TOF-MS has not been used in the field of analysis of drug main components in capsule drugs at present.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention aims to provide a capsule single-particle medicine high-throughput analysis method based on MALDI-TOF-MS. The MALDI-TOF-MS analysis method is used for directly detecting the capsule medicine for the first time, no pretreatment is needed, the sample consumption is small, the analysis speed is high, the detection cost is low, and the continuous, automatic and high-throughput sample injection analysis can be realized. The established method can sensitively and quickly carry out qualitative analysis and uniformity evaluation on the main components of the medicine, and has good practical application value.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a capsule single-particle medicine high-throughput analysis method based on MALDI-TOF-MS comprises the following steps:
spotting the drug main component standard solution on a target plate, drying, performing matrix spotting, and performing MALDI-TOF-MS analysis and detection;
the drug particles in the capsule to be detected are adhered to the target plate through the conductive double-sided adhesive, the conductive adhesive can play a role in fixing an object to be detected and conducting electrons, and MALDI-TOF-MS direct analysis and detection are realized by utilizing the characteristic that the object to be detected in the capsule particles can be ionized under an excitation wavelength;
and identifying the authenticity of the capsule to be detected by comparing the MALDI-TOF-MS graphs of the medicine particles of the capsule to be detected and the medicine main component standard substance.
The inventor finds that when the MALDI-TOF-MS method is adopted to detect the single-particle medicine of the capsule, the detection can be directly carried out without using a matrix or carrying out pretreatment, the use of an organic solvent is avoided to the greatest extent, and the analysis and detection time is greatly shortened because the complex pretreatment process is not required.
In some embodiments, the drug principle standard is diclofenac sodium or itraconazole.
Further, the solvent of the drug main component standard solution is acetonitrile, methanol or ethanol.
Further, the concentration of the drug main component standard solution is 0.8-1.2 mg/mL. The concentration of the standard substance is too low and cannot peak, the standard substance can be further diluted in the using process, and the concentration is unnecessarily high.
Further, the volume of the drug base standard solution dropped on the target plate was 1. mu.l.
In some embodiments, the matrix is 2, 5-dihydroxybenzoic acid (DHB). The inventor finds that the peak-forming effect is better when DHB is used as a substrate through experiments.
Further, the concentration of the matrix is 45-55 mg/mL. Too low a substrate concentration does not produce a peak, too high a substrate concentration and too many peaks affect the chart.
Furthermore, the solvent of the matrix is a mixed solution of acetonitrile and water, and the volume ratio of the acetonitrile to the water is 1:0.8-1.2, and further 1: 1. The inventor finds that the solvent of the matrix can influence the peak effect, the proper solvent can realize good signal-to-noise ratio, and when the solvent of the matrix is a mixed solution of acetonitrile and water, and the volume ratio of the acetonitrile to the water is about 1:1, the good signal-to-noise ratio can be obtained.
In some embodiments, the mass spectrometry conditions for MALDI-TOF-MS are: 80-100% of laser energy, 100-1000 acquisition intervals, a reflection mode as an acquisition mode and 2000 accumulated scanning frequencies.
In some embodiments, the number of the drug particles adhered on the conductive double-sided adhesive is 16 × 24.
Further, the method comprises the step of drawing a heat map of the main component peak of the drug particles based on the detected intensity of the main component characteristic peak of the drug particles to evaluate the uniformity of the drug particles.
The invention has the beneficial effects that:
the method adopts MALDI-TOF-MS technology, successfully establishes a rapid high-throughput screening method for the active ingredients in the capsule medicine with the particle as the inclusion for the first time. The method avoids the use of organic solvent to the maximum extent in the detection process, and the accurate detection and analysis of the active ingredients in the medicine can be rapidly completed within a few minutes from the sample preparation to the result obtaining, thereby realizing high-throughput medicine screening.
The invention establishes a novel MALDI-TOF-MS detection method of the capsule medicine, can quickly, simply and accurately identify the truth of the medicine, and can evaluate the uniformity of the single-particle medicine.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention
FIG. 1 is a MALDI-TOF-MS diagram of a 1.0mg/mL diclofenac sodium standard in example 1 of the present invention.
FIG. 2 is a second-order mass spectrum of a 1.0mg/mL diclofenac sodium standard in example 1 of the present invention.
FIG. 3 is a MALDI-TOF-MS diagram of the diclofenac sodium capsule drug particles in example 1 of the present invention.
FIG. 4 is a chart of the uniformity of single particles of the drug detection of diclofenac sodium capsules based on MALDI-TOF-MS in example 1 of the present invention;
FIG. 5 is a MALDI-TOF-MS chart of a 1.0mg/mL itraconazole standard of example 2 of the present invention.
FIG. 6 is a second-order mass spectrum of 1.0mg/mL itraconazole standard substance in example 2 of the present invention.
FIG. 7 is a MALDI-TOF-MS diagram of itraconazole capsule drug particles of example 2 of the present invention.
Fig. 8 is a thermal map of single particle uniformity for MALDI-TOF-MS based drug testing of itraconazole capsules in example 2 of the present invention.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
Example 1
The MALDI-TOF-MS analysis method of the active pharmaceutical ingredients in the diclofenac sodium capsule comprises the following steps:
(1) instruments and reagents
The mass spectrometer used in the embodiment of the invention is a Bruker rapifleX tissue system; the balance used was a Mettler Toledo XS 105 electronic balance.
The reagents used were chromatographically pure acetonitrile, methanol and ethanol from Merck, Germany; the standard substance is diclofenac sodium chromatographic standard substance of WUDDEST biotechnology limited; the matrices used were 2, 5-dihydroxybenzoic acid (DHB) and alpha-cyano-4-hydroxycinnamic acid (CHCA) matrices from sigma.
The drug samples were collected from Nanjing pharmaceutical factory, and the drug samples were granular.
(2) Sample preparation
The diclofenac sodium standard substance is respectively prepared into a standard substance solution with the concentration of 1.0mg/mL by using acetonitrile, methanol and ethanol.
Preparing the DHB and the CHCA into matrix solutions with the concentration of 20-100mg/mL by using a methanol/water binary mixed solution, an acetone/water binary mixed solution and an acetonitrile/water binary mixed solution respectively.
(3) Conditions of Mass Spectrometry
Bruker rapifleX tissue system mass spectrometer: a positive ion scanning mode; scanning range: m/z is 100-1600; laser wavelength: 355 nm; 50% -100% of laser energy; adopting a reflection mode; sampling rate: 1.25GSs-1(ii) a Acceleration potential: 20kV, vacuum pressure: 3-5x10-7mbar; pulsed ion extraction delay: 100 ns.
Diclofenac sodium [ C14H12Cl2NO2]+The peak was 296 and the qualitative ion peak was 214.
(4) Results
4.1 selection of Standard test matrices
The influence of two solvents, namely CHCA and DHB, on the detection of the diclofenac sodium standard substance is examined. Experiments show that the peak effect of the diclofenac sodium standard substance is better when acetonitrile/water binary mixed solution is used as a solvent and 50mg/mL DHB solution is used as a matrix. Therefore, the present invention selects 50mg/mL DHB acetonitrile/water binary mixed solution as the test matrix of diclofenac sodium standard.
4.2 selection of Standard solvent types
The solubility of three solvents, namely acetonitrile, methanol and ethanol, on the diclofenac sodium standard substance is examined. Experiments show that the methanol and the acetonitrile have better solubility to the diclofenac sodium standard substance. In general terms, methanol is selected as a preparation solvent in the invention.
4.3 optimization of MALDI-TOF-MS Mass Spectroscopy laser energy
The effect of MALDI-TOF-MS laser energy at 50%, 60%, 70%, 80%, 90% and 100% on diclofenac sodium signal was examined. Experiments show that the signal intensity of the diclofenac sodium is enhanced along with the increase of the laser intensity. In comprehensive consideration, the invention selects 80-100% of laser energy.
4.4 optimization of MALDI-TOF-MS Mass Spectrometry Scan frequency
The influence of MALDI-TOF-MS mass spectrum scanning frequency of 200, 500, 1000 and 2000 on the signal of diclofenac sodium is examined. Experiments show that the signal intensity of the diclofenac sodium is enhanced along with the increase of the mass spectrum scanning frequency, and the mass spectrum scanning frequency of 2000 is selected by the invention comprehensively considered.
4.5 MALDI-TOF-MS diagram of diclofenac sodium standard
And detecting the diclofenac sodium standard substance by using an MALDI-TOF-MS method under optimized conditions. Shown in FIG. 1When methanol is used as a preparation solvent, the laser energy is 90%, and the scanning frequency is 2000, 296[ C ] appears in a MALDI-TOF-MS diagram of a 1.0mg/mL diclofenac sodium solution14H12Cl2NO2]+The ion peak was scanned in two stages, and as shown in FIG. 2, the ion peak appeared 214, and thus it was determined that the ion peak was detectable.
4.6 MALDI-TOF-MS diagram of diclofenac sodium capsule drug particles
Pasting a conductive double-sided adhesive tape on a MALDI target plate, opening the capsule, placing the medicine particles in the capsule on a target position in sequence, loading the target plate into a mass spectrometer without any sample pretreatment or matrix addition, adjusting the instrument to an optimal working state according to the MALDI-TOF-MS optimization parameters, and performing mass spectrometry detection, wherein 296[ C ] appears in the MALDI-TOF-MS diagram as shown in figure 314H12Cl2NO2]+Ion peaks successfully realize the detection of the main component of the diclofenac sodium.
4.7 Single particle uniformity heatmap for diclofenac sodium Capsule drug detection
Summary by analysis of diclofenac sodium particles 296[ C ] on 384 target plates14H12Cl2NO2]+Ion peak intensity, a heat map of the main component peak of the drug particles tested was plotted to assess the uniformity of the single particle drug, see figure 4. As can be seen from the figure, the uniformity of the peak intensity of the diclofenac sodium drug particles is better, and the difference of the peak intensity among the particles is smaller.
Example 2
The MALDI-TOF-MS analysis method of the active pharmaceutical ingredients in the itraconazole capsule comprises the following steps:
(1) instruments and reagents
The mass spectrometer used in the embodiment of the invention is a Bruker rapifleX tissue system; the balance used was a Mettler Toledo XS 105 electronic balance.
The reagents used were chromatographically pure acetonitrile, methanol and ethanol from Merck, Germany; the standard substance is itraconazole chromatographic standard substance of Chengdu Design biotechnology limited company; the matrices used were the sigma DHB and CHCA matrices.
The drug samples are collected from Chengdu pharmaceutical factories, and the drug samples are granular.
(2) Sample preparation
And preparing the itraconazole standard substance into a standard substance solution with the concentration of 1.0mg/mL by using acetonitrile, methanol and ethanol respectively.
Preparing the DHB and the CHCA into matrix solutions with the concentration of 20-100mg/mL by using a methanol/water binary mixed solution, an acetone/water binary mixed solution and an acetonitrile/water binary mixed solution respectively.
(3) Conditions of Mass Spectrometry
Bruker rapifleX tissue system mass spectrometer: a positive ion scanning mode; scanning range: m/z is 100-1600; laser wavelength: 355 nm; 50% -100% of laser energy; adopting a reflection mode; sampling rate: 1.25GSs-1(ii) a Acceleration potential: 20kV, vacuum pressure: 3-5x10-7mbar; pulsed ion extraction delay: 100 ns.
[ M + H ] of itraconazole]+The peak was 705 and the qualitative ion peak was 392.
(4) Results
4.1 selection of Standard test matrices
The influence of CHCA and DHB on the detection of itraconazole standard substance is examined. Experiments show that the acetonitrile/water binary mixed solution is used as a solvent, and a 50mg/mL DHB solution is used as a matrix, so that the peak effect on an itraconazole standard product is better. Therefore, the invention selects the DHB acetonitrile/water binary mixed solution of 50mg/mL as the test matrix of the itraconazole standard product.
4.2 selection of Standard solvent types
The solubility of acetonitrile, methanol and ethanol to itraconazole standard substance is examined. Experiments show that methanol and acetonitrile have good solubility to itraconazole standard substance. In general terms, methanol is selected as a preparation solvent in the invention.
4.3 optimization of MALDI-TOF-MS Mass Spectroscopy laser energy
The effects of MALDI-TOF-MS laser energies of 50%, 60%, 70%, 80%, 90% and 100% on itraconazole signals were examined. It was found experimentally that the signal intensity of itraconazole increases with increasing laser intensity. In comprehensive consideration, the invention selects 80-100% of laser energy.
4.4 optimization of MALDI-TOF-MS Mass Spectrometry Scan frequency
The influence of MALDI-TOF-MS mass spectrometry scan frequencies of 200, 500, 1000 and 2000 on the signal of itraconazole was examined. Experiments show that the signal intensity of itraconazole is enhanced along with the increase of the mass spectrum scanning frequency, and the mass spectrum scanning frequency of 2000 is selected by the invention comprehensively considered.
4.5 MALDI-TOF-MS diagram of itraconazole Standard
And detecting the itraconazole standard substance by using an MALDI-TOF-MS method under the optimized condition. As shown in FIG. 5, 705[ M + H ] appeared in the MALDI-TOF-MS chart of 1.0mg/mL itraconazole solution when methanol was used as a formulation solvent, the laser energy was 90%, and the scanning frequency was 2000]+The ion peak was subjected to secondary scanning, and it was judged that 392 ion peaks appeared as shown in fig. 6, and thus were detectable.
4.6 MALDI-TOF-MS diagram of itraconazole capsule drug particles
Pasting a conductive double-sided adhesive tape on a MALDI target plate, opening the capsule, placing the medicine particles in the capsule on a target position in sequence, loading the target plate into a mass spectrometer without any sample pretreatment or matrix addition, adjusting the instrument to an optimal working state according to the MALDI-TOF-MS optimization parameters, and performing mass spectrometry detection, wherein 705[ M + H ] appears in the MALDI-TOF-MS diagram as shown in FIG. 7]+Ion peak, successfully realizes the detection of the main component of itraconazole.
4.7 Single particle uniformity heatmap for itraconazole Capsule drug testing
Summary of itraconazole particles 705[ M + H ] on 384 target plates by analysis]+Ion peak intensity, a heat map of the main component peak of the drug particles tested was plotted to assess the uniformity of the single particle drug, see figure 8. It can be seen from the figure that the uniformity of the peak intensity of the itraconazole drug particles was poor and the difference of the peak intensity among the particles was large.
5. Conclusion
The method adopts MALDI-TOF-MS technology, successfully establishes a rapid high-throughput screening method for the active ingredients in the capsule medicine with the particle content for the first time. The whole process is simple and convenient to operate, and the consumption of the organic solvent is low. From sample preparation to result, accurate detection and analysis of active ingredients in the medicine can be rapidly completed within a few minutes, authenticity of medicine particles can be rapidly, simply and accurately identified, and uniformity evaluation of single-particle medicines is realized.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A capsule single-particle medicine high-throughput analysis method based on MALDI-TOF-MS is characterized in that: the method comprises the following steps:
spotting the drug main component standard solution on a target plate, drying, performing matrix spotting, and performing MALDI-TOF-MS analysis and detection;
adhering the drug particles in the capsule to be detected on a target plate through a conductive double-sided adhesive, and directly performing MALDI-TOF-MS analysis and detection;
and identifying the authenticity of the capsule to be detected by comparing the MALDI-TOF-MS graphs of the medicine particles of the capsule to be detected and the medicine main component standard substance.
2. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 1, characterized by: the standard substance of the main component of the medicine is diclofenac sodium or itraconazole.
3. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 2, characterized in that: the solvent of the drug main component standard solution is acetonitrile, methanol or ethanol.
4. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 3, characterized in that: the concentration of the drug main component standard solution is 0.8-1.2 mg/mL;
further, the volume of the drug main ingredient standard solution dropped on the target plate was 1. mu.l.
5. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 1, characterized by: the matrix is 2, 5-dihydroxy benzoic acid.
6. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 5, characterized in that: the concentration of the matrix is 45-55 mg/mL.
7. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 6, characterized in that: the solvent of the matrix is a mixed solution of acetonitrile and water, and the volume ratio of the acetonitrile to the water is 1:0.8-1.2, and further 1: 1.
8. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 1, characterized by: the mass spectrum conditions of MALDI-TOF-MS are as follows: 80-100% of laser energy, 100-1000 acquisition intervals, a reflection mode as an acquisition mode and 2000 accumulated scanning frequencies.
9. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 1, characterized by: the number of the drug particles stuck on the conductive double-sided adhesive is 16 multiplied by 24.
10. The MALDI-TOF-MS-based capsule single particle drug high-throughput analysis method of claim 1, characterized by: the method also comprises the step of drawing a heat map of the main component peak of the drug particles based on the detection intensity of the main component characteristic peak of the drug particles, and evaluating the uniformity of the drug particles.
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